Investigators at Memorial Sloan Kettering (MSK) recently came across some interesting findings about a particularly aggressive subset of lung cancers—specifically adenocarcinoma—which could lead to new therapeutic drug targets. While targeted therapies are currently available for about one-third of people with lung adenocarcinoma, for the other two-thirds with this type of cancer, there are fewer treatment options. In this new study, the researchers focused their attention on two driver mutations that frequently occur together in the KEAP1 and STK11 genes.
Findings from the new study were published recently in Cell Reports through an article titled, “Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer.” The molecular changes characteristic of these tumors were surprising to the investigators who discovered them: they block a type of cell death called ferroptosis. Cancers with these changes require this blockade to stay alive and grow.
Ferroptosis is a type of programmed cell death that is dependent on iron, which was discovered less than a decade ago, but it has already emerged as an important target for cancer therapies as well as drug treatments for other diseases. Failures in ferroptosis timing often lead to uncontrolled cell growth.
“We really didn’t know what particular vulnerabilities we would find in these cancer cells,” remarked senior study investigator Charles Rudin, MD, PhD, chief of the thoracic oncology service and co-director of the Fiona and Stanley Druckenmiller Center for Lung Cancer Research. “But all of the work we report in this study pointed toward ferroptosis as a key player. Our findings suggest that targeting certain proteins that play a role in the regulation of ferroptosis could lead to new treatments for this cancer.”
The MSK researchers found that alterations in two genes called STK11 and KEAP1 work together to create an environment in which tumor cells are able to grow even when they are receiving signals that would otherwise induce cell death. The combination of mutations in these two genes is found in more than 10% of lung adenocarcinomas, so a drug that could successfully target this alteration would have a meaningful impact.
“We investigated the effects of coordinate STK11 and KEAP1 loss by comparing co-mutant with single mutant and wild-type isogenic counterparts in multiple LUAD models,” the authors wrote. “STK11/KEAP1 co-mutation results in significantly elevated expression of ferroptosis-protective genes, including SCD and AKR1C1/2/3, and resistance to pharmacologically induced ferroptosis. CRISPR screening further nominates SCD (SCD1) as selectively essential in STK11/KEAP1 co-mutant LUAD. Genetic and pharmacological inhibition of SCD1 confirms the essentiality of this gene and augments the effects of ferroptosis induction by erastin and RSL3.”
In the current study, the research team used the gene-editing tool CRISPR to create three types of cells: some of these cells had the gene STK11 knocked out, some had KEAP1 knocked out, and some had both genes knocked out. The team then isolated each of the three cell types and studied them in the lab, including mouse models. The scientists figured out which genes were activated when STK11 and KEAP1 were lost by analyzing the cells’ behaviors.
“Lung cancers tend to be very heterogeneous, so if you don’t do these kinds of controlled experiments, it’s hard to isolate changes attributable to a particular gene or set of genes,” Rudin explained. “By creating these knockouts, it allows us to really focus on cells with these mutations and to link any behaviors we observe to the presence or absence of these factors.”
Interestingly, the team’s observations helped them make the connection to ferroptosis. They found that cells with both the STK11 and KEAP1 mutations also had high levels of proteins already known to make cells resistant to ferroptosis. Rudin and his colleagues pinpointed one of these proteins, called SCD1, as a particularly good target for these tumors.
“Although the current SCD1 inhibitors that we have are not likely to make good drugs, there are many labs at MSK that are actively investigating strategies for targeting ferroptosis in cancer cells,” Rudin concluded. “We hope to find drugs that inhibit the pathways in these tumor cells, ultimately developing a targeted therapy strategy for these particularly difficult cancers.”
